PROJECT SUMMARY/ABSTRACT Following spinal cord injury (SCI), many individuals require ?bowel programs,? consisting of digital stimulation and manual extraction of stool from the rectum, that can take an hour or more to induce defecation, and which are burdensome, time consuming, and undignified. Alternatively, rectal administration of stimulant laxatives, such as bisacodyl or glycerin, can induce defecation 30-60 minutes after insertion of a suppository, but can continue to promote defecation for 2 hours or longer, raising concerns about subsequent fecal incontinence. Furthermore, these surfactants act by permeabilizing the epithelial lining of the rectum and can produce inflammation, which prevents their use on a regular basis. Obviously, there is a serious, unmet medical need for a better method to initiate defecation in individuals with SCI. This Phase 1 application examines the potential of pharmacological activation of rectal afferents to trigger defecation as a proof-of-concept study for an ?intrarectal, on-demand, rapid-onset, short-duration, drug-induced, defecation therapy.? The primary hypothesis is that stimulation of rectal afferent terminals following insertion of a drug-containing dosage form (e.g., a suppository) will trigger excitatory colorectal, and inhibitory rectoanal, reflexes to rapidly induce defecation. A secondary hypothesis is that expulsion of the dosage form, as it is carried along during expulsion of stools, will result in a rapid elimination of the drug immediately upon producing its desired therapeutic effect, thus reducing potential for side effects and/or systemic absorption. For individuals with complete spinal damage at or above the T6 level, this therapy should produce no greater incidence of autonomic dysreflexia than current bowel programs. Based on the clinical literature, it is reasonable to speculate that a drug-induced defecation therapy might be well-tolerated in otherwise healthy individuals who require on-demand, drug-induced defecation. Aim 1 examines the dose range and time course of an intrarectal drug for triggering colorectal activity in acute SCI rats. Aim 2 examines the tolerability and efficacy in conscious rats, as well as the therapeutic utility of the drug with repeated dosing in acute SCI rats. Future Phase 2 studies will evaluate the therapeutic potential in chronic SCI rats, characterize the preclinical safety profile, and initiate development of the final intrarectal formulation for subsequent clinical studies.